HIV infection has become a chronic illness when successfully treated with combined antiretroviral therapy (cART). The long-term health prognosis of aging with controlled HIV infection and HIV-associated neurocognitive disorder (HAND) remains unclear.

With a research focus on chronicity, pre-emptive documentation of episodes of mild neurocognitive dysfunction is needed to determine their long-term prognosis. This strategy would also seek to optimally represent the entire HAND spectrum in therapeutic trials to assess positive and/or negative treatment effects on brain functions.

No individual agent or group of antiretrovirals has unequivocally showed benefits for treating or preventing HAND in the cART era, but there are promising results, which we critically review in light of the increasing importance of chronicity effects.

Prospective randomized clinical trials should be the preferred approach for HIV neurology (neuroHIV) treatment studies, including optimized adaptive randomization approaches to balance HAND clinical categories in treatment arms.